KEGG   DISEASE: Amyotrophic lateral sclerosis (ALS)
Entry
H00058                      Disease                                

Name
Amyotrophic lateral sclerosis (ALS);
Lou Gehrig disease
Description
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive degeneration of motor neurons in the brain and spinal cord. In 90% of patients, ALS is sporadic, with no clear genetic linkage. On the other hand, the remaining 10% of cases show familial inheritance, with mutations in SOD1, TDP43(TARDBP), FUS, or C9orf72 genes being the most frequent causes. In spite of such difference, familial ALS and sporadic ALS have similarities in their pathological features. Proposed disease mechanisms contributing to motor neuron degeneration in ALS are: impaired proteostasis, aberrant RNA processing, mitochondrial disfunction and oxidative stress, microglia activation, and axonal dysfunction.
Category
Neurodegenerative disease
Brite
Human diseases [BR:br08402]
 Nervous system diseases
  Neurodegenerative diseases
   H00058  Amyotrophic lateral sclerosis (ALS)
Human diseases in ICD-11 classification [BR:br08403]
 08 Diseases of the nervous system
  Motor neuron diseases or related disorders
   8B60  Motor neuron disease
    H00058  Amyotrophic lateral sclerosis (ALS)
Pathway
hsa05014  Amyotrophic lateral sclerosis
Network
nt06410  Calcium signaling
nt06412  Unfolded protein response (UPR) signaling
nt06413  Autophagy
nt06414  Apoptosis
nt06415  PI3K signaling
nt06418  Oxidative phosphorylation
nt06419  Microtubule-based transport
nt06420  Ubiquitin-proteasome system
nt06421  Mitophagy
nt06423  Cytoskeletal regulation
nt06424  RNA processing
nt06464  Amyotrophic lateral sclerosis
  Element
N01135  Mutation-caused aberrant SOD1 to intrinsic apoptotic pathway
N01136  Mutation-caused aberrant TDP43 to electron transfer in Complex I
N01138  Mutation-inactivated OPTN to PINK-Parkin-mediated autophagosome formation
N01139  Mutation-inactivated p62 to PINK-Parkin-mediated autophagosome formation
N01141  Mutation-inactivated TBK1 to TBK1-mediated autophagosome formation
N01143  Mutation-inactivated C9orf72 to C9orf72-mediated autophagy initiation
N01144  Mutation-caused aberrant SOD1 to 26S proteasome-mediated protein degradation
N01145  Mutation-inactivated VCP to 26S proteasome-mediated protein degradation
N01146  Mutation-inactivated UBQLN2 to 26S proteasome-mediated protein degradation
N01147  Mutation-caused aberrant SOD1 to ATF6-mediated transcription
N01148  Mutation-caused aberrant SOD1 to IRE1a-XBP1 signaling pathway
N01149  Mutation-caused aberrant SOD1 to PERK-ATF4 signaling pathway
N01150  Mutation-inactivated VAPB to ATF6-mediated transcription
N01151  Mutation-inactivated SIGMAR1 to Ca2+ -apoptotic pathway
N01153  Mutation-caused aberrant GLE1 to nuclear export of mRNA
N01155  Mutation-caused aberrant TDP43 to TDP-43-regulated splicing
N01157  Mutation-caused aberrant FUS to FUS-regulated splicing
N01158  Mutation-caused aberrant DCTN1 to retrograde axonal transport
N01159  Mutation-caused aberrant TUBA4A to retrograde axonal transport
N01160  Mutation-caused aberrant SOD1 to retrograde axonal transport
N01162  Mutation-caused aberrant PFN1 to actin polymerization
N01164  Mutation-inactivated ERBB4 to NRG-ERBB4-PI3K signaling pathway
Gene
(ALS1) SOD1; superoxide dismutase (mutation) [HSA:6647] [KO:K04565]
(ALS1) NEFH; neurofilament (deletion/insertion) [HSA:4744] [KO:K04574]
(ALS1) PRPH; peripherin (deletion) [HSA:5630] [KO:K07607]
(ALS1) DCTN1; dynactin 1 (mutation) [HSA:1639] [KO:K04648]
(ALS2) ALS2; alsin (mutation) [HSA:57679] [KO:K04575]
(ALS4) SETX; senataxin (mutation) [HSA:23064] [KO:K10706]
(ALS5) SPG11 [HSA:80208] [KO:K19026]
(ALS6) FUS; fusion (mutation) [HSA:2521] [KO:K13098]
(ALS8) VAPB; VAMP-associated protein (mutation) [HSA:9217] [KO:K10707]
(ALS9) ANG; angiogenin (mutation) [HSA:283] [KO:K16631]
(ALS10) TARDBP; TAR DNA binding protein (mutation) [HSA:23435] [KO:K23600]
(ALS11) FIG4; FIG4 homolog (mutation) [HSA:9896] [KO:K22913]
(ALS12) OPTN; optineurin (mutation) [HSA:10133] [KO:K19946]
(ALS14) VCP [HSA:7415] [KO:K13525]
(ALS15) UBQLN2 [HSA:29978] [KO:K04523]
(ALS16) SIGMAR1 [HSA:10280] [KO:K20719]
(ALS17) CHMP2B [HSA:25978] [KO:K12192]
(ALS18) PFN1 [HSA:5216] [KO:K05759]
(ALS19) ERBB4 [HSA:2066] [KO:K05085]
(ALS20) HNRNPA1 [HSA:3178] [KO:K12741]
(ALS21) MATR3 [HSA:9782] [KO:K13213]
(ALS22) TUBA4A [HSA:7277] [KO:K07374]
(ALS23) ANXA11 [HSA:311] [KO:K17095]
(FTD-ALS1) C9ORF72 [HSA:203228] [KO:K23609]
(FTD-ALS2) CHCHD10 [HSA:400916] [KO:K22759]
(FTD-ALS3) SQSTM1 [HSA:8878] [KO:K14381]
(FTD-ALS4) TBK1 [HSA:29110] [KO:K05410]
MAPT; microtubule-associated protein tau [HSA:4137] [KO:K04380]
GLE1 [HSA:2733] [KO:K18723]
(ALS/PDC) TRPM7 [HSA:54822] [KO:K04982]
Drug
Riluzole [DR:D00775]
Edaravone [DR:D01552]
Comment
Affected region: motor cortex, brain stem, spinal cord
Microscopic lesion: hyaline inclusions
Other DBs
ICD-11: 8B60.0
ICD-10: G12.2
MeSH: D000690
OMIM: 105400 205100 602433 602099 608030 608627 611895 612069 612577 613435 613954 300857 614373 614696 614808 615515 615426 606070 617839 616208 617839 105550 615911 616437 616439
Reference
PMID:30870681 (gene)
  Authors
Mathis S, Goizet C, Soulages A, Vallat JM, Masson GL
  Title
Genetics of amyotrophic lateral sclerosis: A review.
  Journal
J Neurol Sci 399:217-226 (2019)
DOI:10.1016/j.jns.2019.02.030
Reference
PMID:28980624 (gene)
  Authors
Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH
  Title
Amyotrophic lateral sclerosis.
  Journal
Nat Rev Dis Primers 3:17071 (2017)
DOI:10.1038/nrdp.2017.71
Reference
PMID:19251628 (ALS6)
  Authors
Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE
  Title
Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.
  Journal
Science 323:1208-11 (2009)
DOI:10.1126/science.1165942
Reference
PMID:19251627 (ALS6)
  Authors
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr
  Title
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
  Journal
Science 323:1205-8 (2009)
DOI:10.1126/science.1166066
Reference
PMID:19118816 (ALS11)
  Authors
Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH
  Title
Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.
  Journal
Am J Hum Genet 84:85-8 (2009)
DOI:10.1016/j.ajhg.2008.12.010
Reference
PMID:19081518 (drug)
  Authors
Turner MR, Kiernan MC, Leigh PN, Talbot K
  Title
Biomarkers in amyotrophic lateral sclerosis.
  Journal
Lancet Neurol 8:94-109 (2009)
DOI:10.1016/S1474-4422(08)70293-X
Reference
PMID:18802454 (ALS10)
  Authors
Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R
  Title
Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.
  Journal
PLoS Genet 4:e1000193 (2008)
DOI:10.1371/journal.pgen.1000193
Reference
  Authors
Pasinelli P, Brown RH
  Title
Molecular biology of amyotrophic lateral sclerosis: insights from genetics.
  Journal
Nat Rev Neurosci 7:710-23 (2006)
DOI:10.1038/nrn1971
Reference
  Authors
Gros-Louis F, Gaspar C, Rouleau GA
  Title
Genetics of familial and sporadic amyotrophic lateral sclerosis.
  Journal
Biochim Biophys Acta 1762:956-72 (2006)
DOI:10.1016/j.bbadis.2006.01.004
Reference
PMID:16501576 (ALS9)
  Authors
Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr, Hardiman O
  Title
ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis.
  Journal
Nat Genet 38:411-3 (2006)
DOI:10.1038/ng1742
Reference
PMID:15952898 (ALS1)
  Authors
Valentine JS, Doucette PA, Zittin Potter S
  Title
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.
  Journal
Annu Rev Biochem 74:563-93 (2005)
DOI:10.1146/annurev.biochem.72.121801.161647
Reference
PMID:15478096 (ALS4)
  Authors
Kunst CB
  Title
Complex genetics of amyotrophic lateral sclerosis.
  Journal
Am J Hum Genet 75:933-47 (2004)
DOI:10.1086/426001
Reference
  Authors
Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF
  Title
DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).
  Journal
Am J Hum Genet 74:1128-35 (2004)
DOI:10.1086/421054
Reference
  Authors
Julien JP.
  Title
Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.
  Journal
Cell 104:581-91 (2001)
DOI:10.1016/S0092-8674(01)00244-6
Reference
PMID:20428114 (ALS12)
  Authors
Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H
  Title
Mutations of optineurin in amyotrophic lateral sclerosis.
  Journal
Nature 465:223-6 (2010)
DOI:10.1038/nature08971
Reference
  Authors
Yamashita S, Ando Y
  Title
Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis.
  Journal
Transl Neurodegener 4:13 (2015)
DOI:10.1186/s40035-015-0036-y
Reference
  Authors
Sieh W, Choi Y, Chapman NH, Craig UK, Steinbart EJ, Rothstein JH, Oyanagi K, Garruto RM, Bird TD, Galasko DR, Schellenberg GD, Wijsman EM
  Title
Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates.
  Journal
Hum Mol Genet 18:3725-38 (2009)
DOI:10.1093/hmg/ddp300
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